Increased expression of Profilin potentiates chemotherapeutic agent-mediated tumour regression.

Abstract

Targeted cancer therapy is an alternative to standard chemotherapy for a better prognosis. Although its incompetency for triple-negative breast cancer (TNBC), treatment still relies on classical chemotherapy. Increasing evidence suggest that chemotherapeutic drug-induced toxic effect could be minimised by combinatorial therapy. Profilin's familiar anti-tumorigenic activity can be utilised in combination with the drug to improve efficacy, which could be promising therapeutics to treat TNBC. All-trans retinoic acid (ATRA) in combination with vinblastine was tested on human MDA MB-231 cell line (MB-231) (in vitro) and MB-231 borne breast cancer in nude mice (in vivo). Effects of combination treatment on tumour growth inhibition and apoptosis were examined by tumour volume, histology and PARP cleavage. ATRA-induced transcriptional regulation of profilin had been evaluated by gel-shift and reporter gene assays. Profilin's role in ATRA-induced vinblastine efficacy was validated in profilin-stable and profilin-silenced cells. ATRA binds with RAR/RXR to increase the profilin expression that potentiated cell death by chemotherapeutics. ATRA priming led to vinblastine-mediated potentiation of G2-M phase cell cycle arrest in MB-231 cells and regression of breast cancer in xenograft mice at very low concentration without any adverse effects. Moreover, increased p53 and PTEN but downregulated p65 in the tumour tissues further supported the involvement of profilin for tumour regression. Vinblastine at very low concentration (20 times lesser than the recommended dose for breast cancer therapeutic) significantly regress tumour growth in ATRA-primed mice without any toxic effects suggesting potential combinatorial therapeutics for TNBC.